ABSTRACT Monkey B virus (BV) is a herpesvirus common in macaque (rhesus, cynomolgus) monkeys which are an invaluable resource for biomedical research. When BV is transmitted to humans, ~80% of patients die and survivors frequently experience progressive neurological decline, making BV the single greatest zoonotic danger facing research and veterinary personnel who work with macaques. Drugs currently used to treat BV infections were developed for treatment of herpes simplex virus (HSV) infections, and are all are less effective against BV than HSV. Even when treated with ganciclovir (GCV), the most effective drug, some BV patients still die. Studies in mice also suggest that the current recommended treatment protocol may be flawed, allowing undetected BV infections to invade the central nervous system, resulting in a drastically diminished chance of patient survival. Since new drugs specifically targeted at BV are unlikely to be developed due to a lack of financial incentive, therapy using existing antivirals needs to be optimized. In the proposed study drugs shown to be effective against HSV and some experimental drugs will be tested for in vivo efficacy against BV by systemic administration using a mouse model. Preliminary experiments indicate that drugs applied topically can provide protection against BV that is as effective as systemically administered drugs. In addition, cidofovir (CDV) appears to be more effective against BV than GCV (the most effective drug currently recommended for treatment of BV infections) and an experimental drug having a different mode of action than GCV or CDV is also effective against BV, raising the possibility of its use in a dual drug regimen for added treatment efficacy. These results need to be followed up with additional research to validate use of topical drug delivery as a means of preventing neurological BV infections, use of CDV to treat BV infections, and the potential efficacy of dual drug regimens. This project will produce the needed confirmatory data and test the efficacy of dual drug regimens. The results will serve as a rational scientific basis for possible modification of existing recommendations for treatment of zoonotic BV infections.